Small molecule kinase inhibitors have been rigorously tested to demonstrate their efficacy on tumor cells, but their effects on the interplay between leukocytes and tumors have been largely unstudied due to the use of preclinical xenograft models that lack a competent immune system. T cells, crucial for controlling the growth of immunogenic tumors1, rely upon many of the same signaling pathways targeted by pharmaceutical inhibitors. For instance, engagement of the T cell receptor (TCR) and co-stimulatory receptors activates the Ras-MAPK (mitogen-activated protein kinase) and PI3K-AKT signaling cascades, which are necessary for proliferation and effector function in T cells2. Additionally, the development of myeloid leukocytes also depends upon these pathways3.
The FDA-approved small molecule MEK1/2 inhibitor trametinib represents an example of seemingly paradoxical interactions with host anti-tumor immunity. Studies have shown that proper T cell activation and proliferation are impaired by pharmacological inhibition of MEK signaling, both with trametinib4,5 and other compounds6. These data imply that trametinib would impair anti-tumor T cell function in tumor hosts. However, it was recently found that while trametinib impairs T cell function in vitro, it does not limit the effectiveness of either adoptive cell therapy7 or checkpoint blockade with antibodies against PD-1, PD-L1, and CTLA-47 in mouse models. In fact, in these studies trametinib was able to synergize with immunomodulatory therapies. Additionally, MEK inhibition of tumor cells can lead to increased expression of tumor antigens6,9.
There remains a need in the art for new and effective tools to facilitate treatment of metastatic and refractory cancers and tumors.